Amino boronic acids—amino acids wherein terminal carboxylic groups are replaced by boronic B(OH)2 groups—are important pharmacoisosters of amino acids in various therapeutically promising molecules, mainly for treatment of cancer. For instance, talabostat contains proline boronic acid, bortezomib contains leucine boronic acid. Bortezomib, chemically N-(pyrazin-2-yl)carbonyl-L-phenylalanine-L-leucine boronic acid, is an important proteasome inhibitor and has been clinically approved for use in treating mantle cell lymphoma and multiple myeloma. Recently, many novel molecules containing amino boronic acids, especially leucine boronic acid, have been prepared and biologically tested as described in WO2009/006473 A2.
The synthesis of bortezomib and other amino boronic acid and ester compounds is disclosed in EP0788360 B1, international patent application WO2005/097809 A2, international patent application WO2009/004350 A1, and international patent application WO2009/036281 A2.
EP0788360 B1 describes a general process for preparation of amino boronic acid and ester compounds using (1S,2S,3R,5S)-pinanediol leucine boronate and an amino acid or its derivative as starting materials. As coupling agents 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) were employed.
A synthetic process suitable for a large scale production of amino boronic acid and ester compounds is described in WO2005/097809 A2. The synthesis involves a boronate complex, which is contacted with a Lewis acid under conditions that afford the boronic ester compounds.
WO2009/004350 A1 discloses a high yield synthesis of bortezomib and intermediates for the synthesis thereof. The procedure includes the use of a very high percentage of tetrahydrofuran in the halogenation of the starting compound (S)-pinanediol 2-methylpropane-1-boronate.
WO2009/036281 A2 describes processes for the preparation of substantially pure bortezomib and intermediates thereof. Processes for the preparation of crystalline forms of bortezomib as well as a storage system for bortezomib are also disclosed in said patent application.
In international patent application WO2005/097809 A2, in J. Biol. Chem. 1984, 259, 15106-15114 and in J. Am. Chem. Soc. 1981, 103, 5241-5242 a route for the preparation of α-amino boronic esters, which is known to the person skilled in the art known as the Matteson's synthetic route, is described. Homologation of boronic esters with (dichloromethyl)lithium to form α-chloro boronic esters has been shown to be efficient and result in good chiral selectivity if pinanediol was used as the chiral directing group. The use of the Lewis acid (ZnCl2) as a catalyst and chloride ion scavenger for the rearrangement of the borate intermediate improved the diastereomeric ratio in the α-chloro boronic ester product. α-Chloro boronic esters have been converted to silylated α-amino boronic esters by lithiumhexamethyldisilazane (LiHMDS), which have been desilylated and protonated in situ to the α-amino boronic esters.
An approach for the synthesis of diverse α-amino boronic esters by the highly diastereoselective copper-catalyzed addition of bis(pinacolato)diboron to N-tert-butane sulfinyl aldimines has been disclosed in the J. Am. Chem. Soc. 2008, 130, 6910-6911.
Transformation of 1,1-dihalogenoalkenes to corresponding alkynes and subsequent synthesis of 1-alkynylboranes have been described in Tetrahedron Letters 1972, 13, 3769-3772 and Tetrahedron Letters 1988, 29, 2631-2634.
J. Am. Chem. Soc. 1994, 116, 10302-10303 describes a process for preparing α-substituted 1-alkenyldioxaborolanes starting from 1-alkynyldioxaborolanes by hydrozirconation followed by substitution such as halogenation or carbonylation. The following α-substituted 1-alkenyldioxaborolanes are disclosed in this reference: (E)-2-(1-chloro-3,3-dimethylbut-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, (E)-2-(1-bromo-3,3-dimethylbut-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, (E)-2-(1-iodo-3,3-dimethylbut-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, (E)-2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hept-4-en-3-one, (E)-4,4-dimethyl-1-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-2-en-1-one, (E)-2-(4,4-dimethylpent-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane zirconocene and (E)-2-(hept-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane zirconocene.
There is a need in the art for new intermediate compounds and efficient processes for the preparation of α-substituted boronic esters.